This invention relates to pharmaceutical compositions containing cholinesterase inhibitors, in particular Physostigmine, suitable for buccal or sublingual administration. The oral administration/ingestion of Physostigmine and other cholinesterase inhibitors elicits in the patient a substantially lesser response as compared to an equal dosage administrated parenterally. The lower plasma concentration and resulting reduced efficacy resulting from oral administration most commonly results from the extensive metabolism of the drug during transit from the gastrointestinal tract to the general circulation system. For example, an orally administered drug must pass through the intestinal mucosa and the liver, both of which are abundant in enzymes that will rapidly and effectively metabolize the drug in many ways, thereby reducing the plasma concentration of Physostigmine and its effectiveness to a very short period of time following the oral administration.
Whenever an orally administered drug such as Physostigmine is metabolized rapidly by the gastrointestinal system or liver prior to entering the general circulation, the drug's bioavailability is greatly reduced. This metabolic breakdown of the active drug may be circumvented by administering the drug by an alternative route. Examples of such alternative routes include buccal or sublingual administration. Drugs administered by these routes avoid gut-wall and hepatic metabolism, thereby producing increased bioavailability as compared to oral administration. Neither buccal nor sublingual administration of Physostigmine is known from the prior publications or patents, nor is a beneficial sustained release plasma profile found in prior publications or patents.
It was suggested by K. L. Davis et al. in the Am. J. Psych., 139 (11): 1421-1424, (1982), that until there is a long term administration method maintaining sustained drug plasma concentrations for cholinomimetics (cholinesterase inhibitors) such as Physostigmine in Alzheimer patients, they will be difficult to clinically utilize.
Suitable nontoxic pharmaceutically acceptable carriers for use in the composition of the present buccal or sublingual dosages can be found in Remington's Pharmaceutical Sciences, 17th Edition, 1985. Lozenges for buccal or sublingual administration are described in Modem Pharmaceutics, edited by G. S. Banker and C. T. Rhodes, 1996.
Although there are other compounds absorbed through the buccal/sublingual mucosa, they do not provide a sustained/controlled release plasma profile. For Physostigmine, heretofore, a sustained plasma profile has required a continuous intravenous infusion which is inconvenient and impractical for chronic therapy.
A number of prior publications disclose buccal or sublingual administration of drugs of various types. G. F. Blane et al., in International Conference on Radioactive Isotopes in Pharmacology, 1969, disclose the absorption of etorphine and dihydromorphine from the buccal cavity. D. Bell, M.D., et al. in The Lancet, 1(8420), 71-73, 1985, disclose buccal administration of morphine sulfate. R. S. Todd in British Patent GB2,100,985, published Jan. 12, 1983, discloses a pharmaceutical composition for the sublingual administration of buprenorphine and salts thereof. H. Lowey in U.S. Pat. No. 4,259,314, issued Mar. 31, 1981, discloses a lozenge for buccal administration of dextromethorphan.
A number of other references disclose formulations and delivery systems for buccal administration, including Coumut and Guassens in U.S. Pat. No. 4,020,558, issued May 3, 1977; Porter in U.S. Pat. No. 4,229,447, issued Oct. 21, 1980; Tsuk in U.S. Pat. No. 3,972,995, issued Aug. 3, 1976; Lowey et al. in U.S. Pat. No. 3,870,790, issued Mar. 11, 1975; Russell in U.S. Pat. No. 3,444,858, issued May 20, 1969; Halpern et al. in U.S. Pat. No. 2,698,822, issued Jan. 4, 1955; Geller et al. in U.S. Pat. No. 3,632,743, issued Jan. 4, 1972; and Kissel et al. in United Kingdom Patent Application GB 2,108,841A, published May 25, 1983.
Bender et al, in U.S. Pat. No. 4,539,315, issued Sep. 3, 1985, discloses an aspirin composition for sublingual administration; Libby in U.S. Pat. No. 4,432,975, issued Feb. 21, 1984, discloses a microlozenge containing vitamin B-12 for sublingual administration.
Other publications that have discussed buccal/sublingual administration of drugs include: Culling et al., in the Br. J. Clin. Pharm. 17, 125-131, 1984, disclosing the sublingual administration of the glyceryl trinitrate; Osborne et al., published in the Clin. Pharmac. Ther. 47, 12-19, 1990, on buccal administration of morphine; Rosen et al., published in the Am. J. Drug Alcohol Abuse, 19, 451-464, 1993, on the sublingual administration of Buprenorphine.
In all the cited studies, buccal and sublingual administration provided drug plasma concentrations that were not significantly sustained and decayed with profiles similar to that observed after either parenteral or oral administration.
K. Yukimatsu et al, published in the Drug Dev. and Ind. Pharmacy, 20(4), 503-534, 1994, Development Of A Trans-mucosal Controlled Release Devices For Systemic Delivery Of Antianginal Drugs. These devices require that the dosage form stays in the mouth for a long period of time, which is obviously impractical due to physiological needs such as eating and drinking. Furthermore, S. Asthana et al. suggested in the Clin. Pharmac. And Therap., 58 (3) 1995, that sustained delivery of Physostigmine is the most effective way of delivering this drug. The sustained delivery technique discussed by Asthana et al. was by continuous intravenous infusion. The drawback to the continuous intravenous infusion is the impracticality of this technique whenever continuous and long term administration is indicated.